Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides

ABSTRACT

Aerosol formulations suitable for use in pressurised metered dose inhalers comprise a hydrofluoroalkane propellant, an medicament for inhalation and a surfactant which is a a C 8 –C 16  fatty acid or salt thereof, a bile salt, a phospholipid, or an alkyl saccharide.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/SE95/01542 filed on Dec. 19, 1995.

FIELD OF THE INVENTION

The present invention relates to aerosol formulations suitable for usein pressurised metered dose inhalers (pMDI's). More particularly, itrelates to a formulation including a hydrofluoroalkane (HFA) propellantand a particularly suitable surface active-dispersing agent.

BACKGROUND OF THE INVENTION

Medicaments for treating respiratory and nasal disorders are frequentlyadministered in aerosol formulations through the mouth or nose. Onewidely used method for dispensing such an aerosol formulation involvesmaking a suspension formulation of the medicament as a finely dividedpowder in a liquefied gas known as a propellant. Pressurised metereddose inhalers, or (pMDI's) are normally used to dispense suchformulations to a patient. Surface active agents, or surfactants, arecommonly included in order to aid dispersion of the medicament in thepropellant and to prevent aggregation of the micronised medicamentparticles, and to improve lubrication of the valve.

Until recently, chlorofluorocarbon-containing propellants (CFC's) wereaccepted for use in all pharmaceutical aerosol formulations. Typicalsurfactant dispersing agents used in the CFC formulations were forexample sorbitantrioleate, oleic acid, lecithines, and ethanol. SinceCFC's have been implicated in the destruction of the ozone layer, a newgeneration of propellants has emerged to take their place.

Hydrofluoroalkane (HFA) propellants for example1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane(P227) and 1,1-difluoroethane (P152a) are today considered to be themost promising new propellants. Not only are they environmentallyacceptable, but they also have low toxicity and vapour pressuressuitable for use in aerosols. However, the surfactants commonly usedwith the CFC formulations are not necessarily suitable for use with thenew generation of propellants. Various alternative surfactants have beenproposed.

For example, WO 92/00061 discloses polyethoxylated surfactant for usewith hydrofluorocarbon propellants. WO 91/11173 discloses fluorinatedsurfactants. WO 91/14422 discloses perfluorinated carboxylic acidpropellants for use with hydrofluorocarbon propellants. WO 92/00107discloses the use of a 1,1,1,2-tetrafluoroethane-soluble surfactant with1,1,1,2-tetrafluoroethane propellant.

SUMMARY OF THE INVENTION

It has now been found that certain specific classes of surfactant areparticularly suitable for use with the new generation of propellant.

Accordingly, the present invention provides a pharmaceutical aerosolformulation comprising a hydrofluoroalkane propellant or a mixture ofhydrofluoroalkane propellants, a physiologically effective amount of amedicament for inhalation and a surfactant selected from a C₈–C₁₆ fattyacid or salt thereof, a bile salt, a phospholipid or an alkylsaccharide.

The surfactants employed in the present invention give fine dispersionsin the new propellants, with good stability. The inventive formulationsare therefore useful for administering inhalable medicaments.

Of the fatty acid surfactants and salts thereof, C₈–C₁₆ fatty acidssalts are preferred. Examples of preferred fatty acid salts are sodium,potassium and lysine salts of caprylate (C₈), caprate (C₁₀), laurate(C₁₂) and myristate (C₁₄). As the nature of the counterion is not ofspecial significance, any of the salts of the fatty acids arepotentially useful. A particularly preferred fatty acid salt is sodiumcaprate.

Suitable bile salts may be for example salts of cholic acid,chenodeoxycholic acid, glycocholic acid, taurocholic acid,glycochenodeoxycholic acid, taurochenodeoxycholic acid, deoxycholicacid, glycodeoxycholic acid, taurodeoxycholic acid, lithocholic acid,and ursodeoxycholic acid.

Of the bile salts, trihydroxy bile salts are preferred. More preferredare the salts of cholic, glycocholic and taurocholic acids, especiallythe sodium and potassium salts thereof. The most preferred bile salt issodium taurocholate.

Suitable phospholipids may be for example single-chain phospholipids,for example lysophosphatidylcholines, lysophosphatidylglycerols,lysophosphatidylethanolamines, lysophosphatidylinositols andlysophosphatidylserines or double-chain phospholipids, for examplediacylphosphatidylcholines, diacylphosphatidylglycerols,diacylphosphatidylethanolamines, diacylphosphatidylinositols anddiacylphosphatidylserines.

Of the phospholipids, diacylphosphatidylglycerols anddiacylphosphatidylcholines are preferred, for exampledioctanoylphosphatidylglycerol and dioctanoylphosphatidylcholine.

Suitable alkyl saccharides may be for example alkyl glucosides or alkylmaltosides, for example decyl glucoside and dodecyl maltoside.

The most preferred surfactants are bile salts.

The propellant may comprise for example one or more of1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane(P227) and 1,1-difluoroethane (P152a), optionally in admixture with oneor more other propellants. Prefereably the propellant comprises1,1,1,2-tetrafluoroethane (P134a) or 1,1,1,2,3,3,3-heptafluoropropane(P227), or a mixture of P134a and P227, for example a density-matchedmixture of P134a and P227.

In addition to medicament, propellant and surfactant, a small amount ofethanol (normally up to 5% but possibly up to 20%, by weight) may beincluded in the formulations of the present invention. Ethanol iscommonly included in aerosol compositions as it can improve the functionof the metering valve and in some cases also improve the stability ofthe dispersion.

Medicaments suitable for inclusion in the formulation of the presentinvention are any which may be delivered by inhalation. Suitableinhalable medicaments may include for example β2-adrenoreceptor agonistsfor example salbutamol, terbutaline, rimiterol, fenoterol, reproterol,adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol,salmeterol, formoterol, clenbuterol, procaterol, broxaterol,picumeterol, TA-2005, mabuterol and the like, and theirpharmacologically acceptable esters and salts; anticholinergicbronchodilators for example ipratropium bromide and the like;glucocorticosteroids for example beclomethasone, fluticasone,budesonide, tipredane, dexamethasone, betamethasone, fluocinolone,triamcinolone acetonide, mometasone, and the like, and theirpharmacologically acceptable esters and salts; anti-allergic medicamentsfor example sodium cromoglycate and nedocromil sodium; expectorants;mucolytics; antihistamines; cyclooxygenase inhibitors; leukotrienesynthesis inhibitors; leukotriene antagonists, phospholipase-A2 (PLA2)inhibitors, platelet aggregating factor (PAF) antagonists andprophylactics of asthma; antiarrhythmic medicaments, tranquilisers,cardiac glycosides, hormones, anti-hypertensive medicaments,antidiabetic- antiparasitic- and anticancer- medicaments, sedatives andanalgesic medicaments, antibiotics, antirheumatic medicaments,immunotherapies, antifungal and antihypotension medicaments, vaccines,antiviral medicaments, proteins, peptides, vitamins and others, forexample cell surface receptor blockers, antioxidants, free radicalscavengers and organic salts of N,N′-diacetylcystine.

Combinations of medicaments are also suitable, for example a combinationof formoterol and budesonide.

The medicaments may be used in the form of salts or esters or solvates(hydrates), where appropriate.

Other ingredients may be added into the formulation of the presentinvention, if desired. Such ingredients may be for example otherpharmaceutically active agents, adjuvants, carriers, flavouring agents,buffers, antioxidants, chemical stabilisers and the like.

Preferably the surfactant and medicament are present in the presentinvention in a ratio of approximately 1:50 to 1:0.2. The preferredconcentration of medicament in the formulations of the present inventionis 0.1 mg/ml to 25 mg/ml.

“A medicament for inhalation” means a medicament which is suitable forinhalation and which consists largely of particles in a size rangeappropriate for maximal deposition in the lower respiratory tract (i.e.,under 10 microns). Therefore as much as possible of the medicamentpreferably consists of particles having a diameter of less than 10microns, for example 0.01–10 microns or 0.1–6 microns, for example 0.1–5microns. Preferably at least 50% of the medicament consists of particleswithin the desired size range. For example at least 60%, preferably atleast 70%, more preferably at least 80% and most preferably at least 90%of the medicament consists of particles within the desired size range.

Therefore, the medicament for use in the present invention may have tobe processsed prior to inclusion in the formulations, in order toproduce particles in the desired size range. For example the medicamentmay be micronised, for example out in a suitable mill, for example a jetmill. Alternatively, particles in the desired particle range may beobtained by for example spray drying or controlled crystallisationmethods, for example crystallisation using supercritical fluids.

Preferably, the surfactant for use in the present invention is also inthe desired particle size range.

Where the surfactant and medicament are both micronised, they may be drymixed and then micronised together, or they may be micronised separatelyand then mixed. The propellant and optional ethanol may be addedthereafter, in one or more than one step.

Alternatively a portion of the micronised surfactant may be cold-mixedwith a portion of the propellant and optional ethanol, whereafter themicronised medicament may be added. After mixing in of the medicamentthe remaining surfactant and propellant and optional ethanol may beadded and the suspension filled into appropriate containers.

The aerosol formulation of the present invention is useful for the localor systemic treatment of diseases and may be administered for examplevia the upper and lower respiratory tract, including by the nasal route.As such the present invention also provides said aerosol formulation foruse in therapy; the use of the aerosol formulation in the manufacture ofa medicament for the treatment of diseases via the respiratory tract;and a method for the treatment of a patient in need of therapy,comprising administering to said patient a therapeutically effectiveamount of the aerosol formulation of the present invention.

The following Examples are intended to illustrate, but not limit, theinvention:

Formulations of various medicaments in P134a and/or P227 with differentsurfactants were prepared in order to assess the quality of thesuspensions formed. In the following examples the quality of thesuspension is rated as “acceptable” or “good”. An acceptable suspensionis characterised by one or more of slow settling or separation, readyre-dispersion, little flocculation, and absence of crystallisation ormorphology changes, such that the dispersion is sufficiently stable togive a uniform dosing. A good dispersion is even more stable.

EXAMPLE 1

Micronised formoterol fumarate (1 part) and micronised sodiumtaurocholate (2 parts) (total 5 mg) were added to a plastic coated glassbottle. The bottle was chilled to approximately 40° C. with a mixture ofcarbon dioxide ice and isopropanol, and 10 ml chilled P134a (atapproximately 40° C.) was added. The bottle was sealed with a meteringvalve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 2

Micronised budesonide (10 parts) and micronised sodium taurocholate (2parts) (total 5 mg) were added to a plastic coated glass bottle. Thebottle was chilled to approximately 40° C. with a mixture of carbondioxide ice and isopropanol, and 10 ml chilled P134a (at approximately40° C.) was added. The bottle was sealed with a metering valve andtreated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 3

Micronised salbutamol sulphate (10 parts) and micronised sodiumtaurocholate (2 parts) (total 5 mg) were added to a plastic coated glassbottle. The bottle was chilled to approximately 40° C. with a mixture ofcarbon dioxide ice and isopropanol, and 10 ml chilled P134a (atapproximately −40° C.) was added. The bottle was sealed with a meteringvalve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLE 4

Micronised ipratropium bromide (1 part) and micronised sodiumtaurocholate (2 parts) (total 5 mg) were added to a plastic coated glassbottle. The bottle was chilled to approximately 40° C. with a mixture ofcarbon dioxide ice and isopropanol, and 10 ml chilled P134a (atapproximately 40° C.) was added. The bottle was sealed with a meteringvalve and treated in an ultrasonic bath for about 10 minutes.

A good suspension formed.

EXAMPLES 5–8

Examples 14 were repeated, substituting propellant P227 for P134a. Inall cases, good suspensions formed.

EXAMPLES 9–16

Examples 1–8 were repeated with the following addition: ethanol,approximately 650 μl, was added to the chilled bottle before sealingwith the metering valve. In all cases, acceptable suspensions formed.

1. A pharmaceutical aerosol formulation comprising a hydrofluoroalkane(HFA) propellant; a physiologically effective amount of a medicament forinhalation; and an alkyl saccharide surfactant, wherein the medicamentand the surfactant are suspended in the propellant as a finely dividedpowder.
 2. A pharmaceutical aerosol formulation as claimed in claim 1,wherein the surfactant is selected from the group consisting of an alkylglucoside and an alkyl maltoside.
 3. A pharmaceutical aerosolformulation as claimed in claim 2, wherein the surfactant is selectedfrom the group consisting of decyl glucoside and dodecyl maltoside.
 4. Apharmaceutical aerosol formulation as claimed in claim 1, wherein theformulation comprises a propellant selected from the group consisting of1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane(P227), or 1,1-difluoroethane (P152a).
 5. The pharmaceutical aerosolformulation as claimed in claim 4, wherein the surfactant is decylglucoside.
 6. The pharmaceutical aerosol formulation as claimed in claim4, wherein the surfactant is dodecyl maltoside.
 7. A pharmaceuticalaerosol formulation as claimed in claim 4, wherein the formulationcomprises a propellant mixture comprising 1,1,1,2-tetrafluoroethane(P134a) and 1,1,1,2,3,3,3-heptafluoropropane (P227).
 8. A pharmaceuticalaerosol formulation as claimed in claim 7, wherein the formulationcomprises a density-matched propellant mixture of1,1,1,2-tetrafluoroethane (P134a) and 1,1,1,2,3,3,3-heptafluoropropane(P227).
 9. The pharmaceutical aerosol formulation as claimed in claim 7,wherein the surfactant is decyl glucoside.
 10. The pharmaceuticalaerosol formulation as claimed in claim 7, wherein the surfactant isdodecyl maltoside.
 11. A pharmaceutical aerosol formulation as claimedin claim 1, wherein the medicament is selected from the group consistingof a β2-adrenoreceptor agonist, an anticholinergic bronchodilator, and aglucocorticosteroid.
 12. A pharmaceutical aerosol formulation as claimedin claim 1, wherein the medicament is selected from the group consistingof salbutamol, terbutaline, rimiterol, fenoterol, reproterol,adrenaline, pirbuterol, isoprenaline, orciprenaline, bitolterol,salmeterol, formoterol, clenbuterol, procaterol, broxaterol,picumeterol, mabuterol, ipratropium bromide, beclomethasone,fluticasone, budesonide, tipredane, dexamethasone, betamethasone,fluocinolone, triamcinolone acetonide, mometasone, and pharmacologicallyacceptable esters and salts thereof.
 13. A pharmaceutical aerosolformulation as claimed in claim 1, wherein the medicament is selectedfrom the group consisting of anti-allergic medicaments, expectorants,mucolytics, antihistamines, cyclooxygenase inhibitors, leukotrienesynthesis inhibitors, leukotriene antagonists, phospholipase-A2 (PLA2)inhibitors, platelet aggregating factor (PAF) antagonists, prophylacticsof asthma, antiarrhythmic medicaments, tranquilisers, cardiacglycosides, hormones, anti-hypertensive medicaments, antidiabeticmedicaments, antiparasitic medicaments, anticancer medicaments,sedatives, analgesic medicaments, antibiotics, antirheumaticmedicaments, immunotherapeutic agents, antifungal medicaments,antihypotension medicaments, vaccines, antiviral medicaments, proteins,peptides, vitamins, cell surface receptor blockers, antioxidants, freeradical scavengers, and organic salts of N,N′-diacetylcystine.
 14. Apharmaceutical aerosol formulation as claimed in claim 1, includingethanol in an amount of up to 20% by weight of propellant andsurfactant.
 15. A pharmaceutical aerosol formulation as claimed in claim1, including ethanol in an amount of up to 5% by weight of propellantand surfactant.
 16. A pharmaceutical aerosol formulation as claimed inclaim 1, further comprising a substance selected from the groupconsisting of adjuvants, carriers, flavouring agents, buffers,antioxidants and chemical stabilisers.
 17. A pharmaceutical aerosolformulation as claimed in claim 1, wherein at least 50% of themedicament consists of particles having a diameter of 0.01–10 microns.18. A pharmaceutical aerosol formulation as claimed in claim 17, whereinat least 70% of the medicament consists of particles having a diameterof 0.01–10 microns.
 19. A pharmaceutical aerosol formulation as claimedin claim 17, wherein at least 90% of the medicament consists ofparticles having a diameter of 0.01–10 microns.
 20. A pharmaceuticalaerosol formulation as claimed in claim 1, wherein at least 50% of themedicament consists of particles having a diameter of 0.1–6 microns. 21.A pharmaceutical aerosol formulation as claimed in claim 20, wherein atleast 70% of the medicament consists of particles having a diameter of0.01–6 microns.
 22. A pharmaceutical aerosol formulation as claimed inclaim 20, wherein at least 90% of the medicament consists of particleshaving a diameter of 0.01–6 microns.
 23. A pharmaceutical aerosolformulation as claimed in claim 1, wherein at least 50% of themedicament consists of particles having a diameter of 0.1–5 microns. 24.A pharmaceutical aerosol formulation as claimed in claim 1, wherein theconcentration of medicament in the formulation is 0.1 mg/ml to 25 mg/ml.25. A pharmaceutical aerosol formulation as claimed in claim 1, whereinthe ratio of surfactant to medicament is in the range of 1:50 to 1:0.2.26. A pharmaceutical aerosol formulation as claimed in claim 1, theformulation comprising a physiologically effective amount of each of aβ2-adrenoreceptor agonist and a glucocorticosteriod.
 27. Apharmaceutical aerosol formulation as claimed in claim 26, furthercomprising a physiologically effective amount of an anticholinergicbronchodilator.
 28. A pharmaceutical aerosol formulation as claimed inclaim 1, the formulation comprising a physiologically effective amountof each of (a) formoterol, or a salt, ester, solvate, or solvate of asalt or ester thereof; and (b) budesonide, or a salt, ester, solvate, orsolvate of a salt or ester thereof.
 29. A pharmaceutical aerosolformulation as claimed in claim 1, the formulation comprising aphysiologically effective amount of each of (a) formoterol, or a salt,ester, solvate, or solvate of a salt or ester thereof; and (b)mometasone, or a salt ester, solvate, or solvate of a salt or estertherefor.
 30. A pharmaceutical aerosol formulation as claimed in claim1, the formulation comprising a physiologically effective amount of eachof (a) formoterol, or a salt, ester, solvate, or solvate of a salt orester thereof; and (b) fluticasone, or a salt, ester, solvate, orsolvate of a salt or ester thereof.
 31. A pharmaceutical aerosolformulation as claimed in claim 1, the formulation comprising aphysiologically effective amount of each of (a) salmeterol, or a salt,ester, solvate, or solvate of a salt or ester thereof; and (b)fluticasone, or a salt, ester, solvate, or solvate of a salt or esterthereof.
 32. The pharmaceutical aerosol formulation as claimed in claim1, wherein the surfactant is decyl glucoside.
 33. The pharmaceuticalaerosol formulation as claimed in claim 1, wherein the surfactant isdodecyl maltoside.
 34. A pharmaceutical aerosol formulation as claimedin claim 1, the formulation comprising a physiologically effectiveamount of each of (a) formoterol and (b) budesonide.
 35. Apharmaceutical aerosol formulation as claimed in claim 1, wherein theformulation comprises a physiologically effective amount of each of (a)an anticholinergic bronchodilator and (b) a β2-adrenoreceptor agonist.36. A pharmaceutical aerosol formulation as claimed in claim 1, whereinthe formulation comprises a physiologically effective amount of each of(a) an anticholinergic bronchodilator and (b) a glucocorticosteroid. 37.A method for the manufacture of a pharmaceutical aerosol formulation asclaimed in claim 1, comprising the steps of: providing a mixture of themedicament and the surfactant in a vessel; adding hydrofluoroalkane(HFA) propellant to the vessel; and mixing the propellant with themedicament/surfactant mixture to produce amedicament/surfactant/propellant mixture in which the medicament and thesurfactant are suspended in the propellant as a finely divided powder.38. The method of claim 37, further comprising the step of mixingadditional HFA propellant with the medicament/surfactant/propellantmixture to produce a further mixture in which the medicament and thesurfactant are suspended in propellant as a finely divided powder.
 39. Amethod for the treatment of a patient in need of therapy with an inhaledmedicament, comprising administering to said patient a therapeuticallyeffective amount of a pharmaceutical aerosol formulation comprising aHFA propellant; a physiologically effective amount of a medicament forinhalation; and an alkyl saccharide surfactant, wherein the medicamentand the surfactant are suspended in the propellant as a finely dividedpowder.
 40. The method of claim 39, wherein the formulation comprises apropellant selected from the group consisting of1,1,1,2-tetrafluoroethane (P134a), 1,1,1,2,3,3,3-heptafluoropropane(P227), and 1,1-difluoroethane (P152a).
 41. The method of claim 39,wherein the surfactant is selected from the group consisting of an alkylglucoside and an alkyl maltoside.
 42. The method of claim 39, whereinthe medicament is selected from the group consisting of aβ2-adrenoreceptor agonist, an anticholinergic bronchodilator, and aglucocorticosteroid.
 43. The method of claim 39, wherein the medicamentis selected from the group consisting of anti-allergic medicaments,expectorants, mucolytics, antihistamines, cyclooxygenase inhibitors,leukotriene synthesis inhibitors, leukotriene antagonists,phospholipase-A2 (PLA2) inhibitors, platelet aggregating factor (PAF)antagonists, prophylactics of asthma, antiarrhythmic medicaments,tranquilisers, cardiac glycosides, hormones, anti-hypertensivemedicaments, antidiabetic medicaments, antiparasitic medicaments,anticancer medicaments, sedatives, analgesic medicaments, antibiotics,antirheumatic medicaments, immunotherapeutic agents, antifungalmedicaments, antihypotension medicaments, vaccines, antiviralmedicaments, proteins, peptides, vitamins, cell surface receptorblockers, antioxidants, free radical scavengers, and organic salts ofN,N′-diacetylcystine.
 44. The method of claim 39, wherein the ratio ofsurfactant to medicament is in the range of 1:50 to 1:0.2.
 45. Themethod of claim 39, wherein the formulation comprises a physiologicallyeffective amount of each of a β2-adrenoreceptor agonist and aglucocorticosteriod.
 46. The method of claim 45, wherein the formulationfurther comprises a physiologically effective amount of ananticholinergic bronchodilator.
 47. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)formoterol, or a salt, ester, solvate, or solvate of a salt or esterthereof; and (b) budesonide, or a salt, ester, solvate, or solvate of asalt or ester thereof.
 48. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)formoterol, or a salt, ester, solvate, or solvate of a salt or esterthereof; and (b) mometasone, or a salt ester, solvate, or solvate of asalt or ester therefor.
 49. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)formoterol, or a salt, ester, solvate, or solvate of a salt or esterthereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of asalt or ester thereof.
 50. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)salmeterol, or a salt, ester, solvate, or solvate of a salt or esterthereof; and (b) fluticasone, or a salt, ester, solvate, or solvate of asalt or ester thereof.
 51. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)formoterol and (b) budesonide.
 52. The method of claim 39, wherein theformulation comprises a physiologically effective amount of each of (a)an anticholinergic bronchodilator and (b) a β2-adrenoreceptor agonist.53. The method of claim 39, wherein the formulation comprises aphysiologically effective amount of each of (a) an anticholinergicbronchodilator and (b) a glucocorticosteroid.